A Cochrane review of 76 trials measured, between the 5th and 13th week following hyaluronic acid infiltration into the knee, pain reduction of 28 to 54% compared to baseline. A meta-analysis of 169 trials, published in 2022 in the BMJ, concludes however that the difference with placebo injection remains too small to be perceived. These two results do not contradict each other: they measure two different things, and understanding them helps you decide with your doctor.
This guide brings together what studies identified via PubMed show: efficacy, placebo effect, expert society opinions, number of injections, onset and duration of effect, corticosteroids and PRP, side effects, then oral hyaluronic acid and the best-supported options (exercise, weight loss, plant-based treatments evaluated in trials).
Infiltrations : hyaluronic acid injected into an arthritic knee provides relief with maximum benefit between the 5th and 13th week, and performs better than corticosteroids after the 8th week. But a saline injection also provides relief: in large trials, the difference with placebo is only 2 mm on a scale of 100. OARSI accepts it on a case-by-case basis; the American College of Rheumatology advises against it except when other options have failed. Infection remains rare.
Other options : exercise, especially quadriceps strengthening, reduces pain by 12 points on a scale of 100 according to 44 trials, and weight loss eases the load on the knee. By mouth, hyaluronic acid has been tested at 48 to 240 mg daily in small trials with fragile results. No supplement has been compared to infiltration.
- What hyaluronic acid does in the knee
- Infiltration: what meta-analyses measure
- The placebo effect of injection
- Expert societies: diverging opinions
- One injection or three to five?
- Onset of action, duration of effect, and repeated courses
- Corticosteroids, PRP, combination: the comparisons
- Side effects and precautions after injection
- Hyaluronic acid by mouth
- Exercise and weight loss: the basic treatments
- Devil's claw, turmeric, ginger, collagen
- Choosing well, with your doctor
- Frequently Asked Questions
What hyaluronic acid does in the knee
Hyaluronic acid is a long chain of sugars that reaches its highest concentration in synovial fluid, inside the joints: 3 to 4 mg per milliliter. It gives this fluid its viscosity and serves as a lubricant, so effective that friction between cartilage surfaces becomes nearly zero.
This lubrication becomes depleted over the years. In synovial fluid from donors aged 23 to 91 without osteoarthritis, hyaluronic acid concentration decreased by 10.5% per decade, and its fraction of highest molecular weight, from 2.5 to 7 million daltons, by 9.4% per decade. In osteoarthritis, the concentration and molecular weight of synovial hyaluronic acid decrease, which impairs its elastic and viscous properties.
This is the rationale for viscosupplementation : injecting into the joint manufactured hyaluronic acid, extracted from rooster combs or obtained by fermentation, to partially restore these properties.
Trials primarily evaluate pain and function, using questionnaires such as the WOMAC score. The longest, over 40 months, does not allow determination of whether hyaluronic acid modifies the course of osteoarthritis, as acknowledged by its authors.
Injection: what meta-analyses measure
The 2006 Cochrane review assembled 76 randomized trials, of which 40 were placebo-controlled. Between week 5 and week 13, pain decreased by 28 to 54% and function improved by 9 to 32% compared to baseline, with efficacy comparable to oral anti-inflammatory drugs and more durable than that of injected corticosteroids.
In 2015, a network meta-analysis of 137 studies ranked injected hyaluronic acid at the top of pharmacological treatments for pain at 3 months, with an effect size of 0.63 versus oral placebo, compared to 0.18 for acetaminophen, perhaps partly due, according to the authors, to a placebo effect specific to injection.
Analyses accounting for trial quality are more modest. In 2012, a meta-analysis of 89 trials found an effect of −0.37 across 71 of them, but with publication bias : unpublished trials showed nearly null effect (−0.03), and the 18 large blinded trials (5,094 patients) an effect of −0.11, deemed clinically irrelevant. Serious adverse effects were more frequent than with placebo (relative risk of 1.41).
Across 169 trials and 21,163 participants, the 24 large placebo-controlled trials (8,997 participants) found a pain reduction of 2 mm on a 100 mm scale compared to placebo injection, an effect size of −0.08, below the threshold for perceptible difference set by the authors (−0.37). Serious adverse effects were more frequent than with placebo (relative risk of 1.49), and the authors conclude that these data do not support widespread use of viscosupplementation.
Pereira TV, Jüni P, Saadat P, et al. BMJ 2022;378:e069722. DOI: 10.1136/bmj-2022-069722
| Analysis | Data | Pain outcome |
|---|---|---|
| Cochrane Review, Bellamy, 2006 | 76 trials | 28 to 54% reduction in pain compared to baseline, over 5 to 13 weeks |
| Meta-analysis, Rutjes, 2012 | 89 trials, 12,667 adults | −0.37 across 71 trials, −0.11 in large blinded trials |
| Network, Bannuru, 2015 | 137 studies, 33,243 participants | 0.63 versus oral placebo, at 3 months |
| Meta-analysis, Pereira, 2022 | 169 trials, 21,163 participants | −0.08 versus placebo in 24 large trials |
Effect size measures the difference between two groups relative to the variability of measurements. By convention, 0.2 corresponds to a small effect, 0.5 to a medium effect, and 0.8 to a large effect. According to the authors, a favorable result is written with or without a minus sign: only the difference from zero matters.
The placebo effect of injection
In osteoarthritis, placebo provides significant relief: a meta-analysis of 198 trials (16,364 patients receiving placebo) measured an effect size of 0.51 on pain, compared to 0.03 without treatment, with a more pronounced effect when placebo is administered by injection or needle.
In a meta-analysis of 14 placebo groups from randomized trials (1,076 patients), saline solution injected into the knee improved pain compared to pre-injection levels, with statistical significance at 3 and 6 months and clinical significance at 6 months. In the AMELIA trial, detailed below, 65.8% of patients receiving placebo met improvement criteria after 40 months, compared to 80.5% receiving hyaluronic acid.
Compared to baseline, infiltration relieves many patients; compared to placebo injection, its own effect is small. The perceived benefit combines both: the American College of Rheumatology refers to contextual effects of injection.
Professional societies: divergent opinions
TheOARSI (Osteoarthritis Research Society International) places in 2019 patient education and structured exercise, with or without weight management, at the core of knee osteoarthritis treatment. Corticosteroid and hyaluronic acid infiltrations are listed at level 1B or 2 depending on the patient's other conditions: options to be considered on a case-by-case basis.
TheAmerican College of Rheumatology issued the same year a conditional recommendation against hyaluronic acid injected into the knee: limited to trials with low risk of bias, the effect versus saline approaches zero. Infiltration can be discussed through shared decision-making when other options have failed: exercise, topical and oral anti-inflammatories, injected corticosteroids. The latter are strongly recommended.
Who responds best? In an observational study of 102 patients with mild to moderate osteoarthritis, 57% responded. Early-stage osteoarthritis (grades 1 and 2), a response from the first injection, and age 60 or older at least doubled the chances of responding. Non-responders more often had a prosthesis later (30%, compared to 12%), an association that does not prove a causal link.
The Kellgren and Lawrence classification ranges from 0, no sign, to 4, severe osteoarthritis, according to X-ray. The trials cited here primarily recruited grades 2 and 3.
One injection or three to five?
Depending on the product, hyaluronic acid is injected as a single dose or in weekly series, most often 3 to 5 injections. Meta-analyses comparing these regimens conflict, and the main ones have ties with manufacturers.
In a meta-analysis of 30 publications, two of whose authors worked for a manufacturer, series of 2 to 4 injections showed the greatest effect compared to saline. Single injection did not reach statistical significance; series of 5 or more injections reached significance only at 6 months, with more treatment-related adverse effects (relative risk of 1.67).
Conversely, a meta-analysis of 28 studies of products in single injection (4,129 patients), signed by an author working for a pharmaceutical company, concludes that single injection performs equally with series. Its methodology, which includes studies without a control group compared retrospectively to placebos from other trials, is less robust.
The molecular weight could matter. In a network meta-analysis where several authors worked for a manufacturer, high molecular weight hyaluronic acid (6,000 kDa or more) reduced pain compared to placebo (−0.57), unlike low molecular weight forms of less than 750 kDa (−0.23, not significant).
| Regimen | Result compared to placebo | Study |
|---|---|---|
| 1 injection | Not significant at 3 and 6 months | Concoff, 2017 |
| 2 to 4 injections | −0.76 at 3 months, −0.36 at 6 months | Concoff, 2017 |
| 5 or more injections | Significant at 6 months only, more adverse effects | Concoff, 2017 |
| Single injection products | 0.30 at 3 months, 0.39 at 6 months | Vincent, 2019 |
| High molecular weight | −0.57 | Hummer, 2020 |
| Low molecular weight | −0.23, not significant | Hummer, 2020 |
The regimen depends on the product chosen by the physician: the data do not allow us to assert that a single injection is equivalent to a series, or vice versa. Ask for the product name and expected timeframe.
Time to action, duration of effect, and repeated courses
Hyaluronic acid does not work immediately. In a meta-analysis of 7 trials (606 participants) comparing it to injected corticosteroids, corticosteroids performed better at 2 weeks (effect size of 0.39 in their favor), the two were equivalent at 4 weeks, then hyaluronic acid gained the advantage: 0.22 at 8 weeks (not significant), 0.35 at 12 weeks and 0.39 at 26 weeks. The Cochrane review places maximum benefit between week 5 and week 13.
The effect remains measurable up to 6 months in trials. Beyond that, a 40-month trial tested repeated courses.
In 306 patients with grade 2 or 3 knee osteoarthritis, four courses of five weekly injections of 900,000 dalton hyaluronic acid, spaced 6 months apart then one year apart, were compared to saline injections. At 40 months, 80.5% of treated patients met OARSI improvement criteria, compared to 65.8% under placebo. The proportion of responders increased with each course, from 71.1% to 80.5%, and the effect persisted at least one year after the last course. Treatment-related adverse effects occurred in 9.8% of patients, compared to 9.1% under placebo, with none being serious.
Navarro-Sarabia F, Coronel P, Collantes E, et al. Ann Rheum Dis 2011;70(11):1957-1962. DOI: 10.1136/ard.2011.152017
In that trial, courses were given at fixed intervals, even without symptoms. In practice, the decision to repeat treatment is made with the physician, based on the response to the previous course.
Corticosteroids, PRP, combination: the comparisons
According to the 2015 Cochrane review (27 trials, 1,767 participants), injected corticosteroids reduce pain compared to placebo with an effect size of −0.40: moderate at 1 to 2 weeks (−0.48), small at 13 weeks (−0.22), absent at 26 weeks (−0.07). The evidence is judged to be of low quality, but the American College of Rheumatology favors them over other injections.
Platelet-rich plasma, or PRP, is prepared from the patient's blood. A meta-analysis of 18 trials (811 patients on PRP, 797 on hyaluronic acid, followed for an average of 11 months) found a 44.7% improvement in WOMAC score under PRP, compared to 12.6% under hyaluronic acid. The most rigorous placebo-controlled trial tempered this result.
In 288 patients aged 50 and over with grade 2 or 3 knee osteoarthritis, three weekly injections of leukocyte-poor PRP did not perform better than saline: at 12 months, pain had decreased by 2.1 points on a 10-point scale under PRP and by 1.8 points under placebo, a non-significant difference, with no effect on cartilage volume measured on MRI.
Bennell KL, Paterson KL, Metcalf BR, et al. JAMA 2021;326(20):2021-2030. DOI: 10.1001/jama.2021.19415
The American College of Rheumatology advises against PRP, due to lack of standardization of preparations. As for combinations, a network meta-analysis of 37 trials (5,089 patients) followed for at least one year ranks PRP combined with hyaluronic acid at the top, ahead of PRP alone, hyaluronic acid and corticosteroid combination, then hyaluronic acid alone. This ranking often relies on indirect comparisons.
| Injection | Effect profile | Study benchmarks |
|---|---|---|
| Corticosteroids | Fast, nil at 26 weeks | −0.40, weak evidence; strong ACR recommendation |
| Hyaluronic acid | Slower, better than corticosteroids from 12 to 26 weeks | −0.08 vs placebo in large trials; ACR against, OARSI case by case |
| PRP | Divergent results | Superior to hyaluronic acid in 18 trials, equal to placebo in RESTORE |
| Combinations | Ranked at the top at one year | Comparisons mostly indirect, to be confirmed |
Side effects and precautions after injection
The most frequent reactions are local : pain at the injection site and moderate swelling, most often temporary, according to a review of safety data for marketed products. More rarely, pseudogout attacks, anaphylactoid reactions—that is, severe allergic reactions—and severe acute inflammatory reactions, called pseudoseptic because they mimic an infection, described with a chemically modified preparation to increase its molecular weight; an immune mechanism is suggested.
In the AMELIA trial, treatment-related adverse effects occurred in 9.8% of treated patients and 9.1% under placebo. Recent meta-analyses note an excess ofserious adverse effects compared to placebo (relative risk of 1.41 in 2012, 1.49 in 2022); in a safety meta-analysis, the estimate remained the same (1.78) in trials without other osteoarthritis treatment, without reaching significance, with a low to moderate level of certainty.
Joint infection, or septic arthritis, remains rare: in a large American cohort, it was coded in at most 0.5% of patients within 90 days following an injection of hyaluronic acid or corticosteroids, two groups not compared with each other.
No cited study tested the course of action after injection. Here are practical tips, to be adapted to your doctor's instructions: report any allergies and medications before injection, particularly anticoagulants; rest the knee for 24 to 48 hours, without intense sport, long walks or carrying heavy loads, without immobilizing it; ask which pain reliever to take if discomfort occurs; then gradually resume walking and exercises.
Fever or chills, red knee, warm and very swollen, pain that increases rather than decreases in the days following: these signs may indicate an infection or acute inflammatory reaction and warrant medical attention the same day. Widespread rash, facial swelling or breathing difficulty require emergency care: call 15.
Hyaluronic acid by mouth
When swallowed, hyaluronic acid is not absorbed as-is: gut bacteria break it down into fragments, some of which may be absorbed. This is not a direct supply to the knee.
A 2016 review identifies 13 publications testing 48 to 240 mg of hyaluronic acid daily for 2 weeks to 12 months, most often in a few dozen participants, sometimes with ingredient blends; several of its authors worked for a manufacturer. Several of the trials described report a greater reduction in pain than with placebo.
In 60 patients aged 50 and over with grade 2 or 3 knee osteoarthritis, 200 mg daily of hyaluronic acid of approximately 900,000 daltons, in 4 capsules, were compared to placebo for 12 months, with all participants performing daily quadriceps strengthening exercises. Symptoms improved in both groups, with no significant difference in the 38 patients analyzed. In the 21 patients aged 70 or younger, the score was significantly better with hyaluronic acid at 2 and 4 months, but not at 6 and 12 months.
Tashiro T, Seino S, Sato T, et al. ScientificWorldJournal 2012;2012:167928. DOI: 10.1100/2012/167928
The benefit was thus limited to a subgroup, over a few months, with daily exercise. Our Marine collagen and hyaluronic acid in capsules provides 200 mg of hyaluronic acid per 4 capsules daily, combined with 1,208 mg of Naticol® marine collagen, 160 mg of vitamin C and 3.96 mg of manganese. This is not the tested product, which contained hyaluronic acid alone, and the trial result cannot be attributed to it.
Not all trials are positive: in 80 patients suffering from moderate knee pain, a drink combining 50 mg of hyaluronic acid, 750 mg of glucosamine and 250 mg of chondroitin, taken for 8 weeks, did not perform better than placebo.
No study has compared oral hyaluronic acid to injection. One is a one-time medical procedure; the other is a daily intake over several months, which can be part of a routine alongside exercise. Our comparison serum or capsules details the forms of hyaluronic acid.
Exercise and weight loss: the foundational treatments
According to the 2015 Cochrane review, high-quality evidence from 44 trials (3,537 participants) shows that exercise reduces pain by 12 points out of 100, an effect size of −0.49, close to a medium effect, and improves function by 10 points. A benefit of 6 points on pain persists 2 to 6 months after the program, an effect that the authors consider comparable to that of anti-inflammatory drugs.
A meta-regression of 48 trials favors exercises targeting the quadriceps (effect size of 0.85, versus 0.39 for overall leg work) and supervised programs at least 3 times per week (0.68 versus 0.41), regardless of radiological severity. Preserving muscle becomes even more important with age: see our article on sarcopenia.
Weight loss acts on knee mechanics. Among 142 overweight older adults suffering from knee osteoarthritis, each kilogram lost was associated with a decrease of approximately 40 newtons in knee compression force at each step, roughly four times the weight lost. In the IDEA trial (454 participants age 55 and older, 18 months), the diet and exercise group lost 11.4% of their weight and had less pain than the exercise-only group. According to the American College of Rheumatology, a loss of 5% of body weight or more can already be accompanied by improvement. See our guide to losing weight after 50.
The program below is practical advice built from trial parameters, to be validated by a physical therapist in case of significant pain.
Harpagophytum, turmeric, ginger, collagen
<<<39>>> Harpagophytumharpagophytum, or devil's claw, is a plant from southern Africa whose root is used. A systematic review of 12 trials concludes, based on a single trial of 89 patients, moderate evidence for harpagophytum powder providing approximately 60 mg of harpagoside per day in osteoarthritis of the spine, hip, and knee.
In 122 patients with knee or hip osteoarthritis, 2,610 mg daily of cold-pressed ground devil's claw root powder, providing 57 mg of harpagoside daily according to a review, were compared over 4 months to diacerein, a slow-acting osteoarthritis medication. Pain and functional index improved equally in both groups, with less use of anti-inflammatories and fewer cases of diarrhea with devil's claw (8.1% versus 26.7%). The trial was conducted by the manufacturer of the tested product.
Chantre P, Cappelaere A, Leblan D, et al. Phytomedicine 2000;7(3):177-183. DOI: 10.1016/S0944-7113(00)80001-X
Our Organic Devil's Claw provides 1,200 mg of organic root powder from Namibia daily: a lower dose than in this trial, and a powder not standardized for harpagoside content, so the trial's results are not directly applicable to it. A review of 28 trials found minor adverse effects in approximately 3% of patients, mainly digestive, with no excess compared to placebo. It is not recommended in cases of stomach or duodenal ulcers and gallstones.
Our Joint Gel combines an extract of devil's claw root and camphor: a hazelnut-sized amount massaged 1 to 2 times daily, for external use, to be avoided before 30 months, on wounds, during pregnancy and breastfeeding.
Turmeric. In 70 patients with knee osteoarthritis with effusion, 2 capsules daily of a turmeric extract for 12 weeks reduced pain by 9.1 mm on a 100-point scale more than placebo, without reducing the effusion; the trial was co-financed by the manufacturer. See our guide on turmeric.
Ginger. A meta-analysis of 5 trials (593 patients) measures a small effect on pain (−0.30), with twice as many treatment discontinuations as with placebo. See our article ginger and osteoarthritis.
Collagen. In 250 patients with knee osteoarthritis, a controlled trial of 10 g of hydrolyzed collagen daily for 6 months reported an improvement in pain, especially in participants with more advanced osteoarthritis and low meat consumption; at the same dose for 12 weeks, collagen peptides performed no better than placebo in 167 active adults complaining of knee pain. A meta-analysis of placebo-controlled trials, all forms of oral collagen combined, found a reduction in pain on visual analog scale (mean difference of −16.57) and total WOMAC score, with no significant effect on WOMAC pain and function subscores. Our Marine Collagen and Hyaluronic Acid Powder provides 10 g of Naticol® marine collagen daily, with 210 mg of hyaluronic acid; these trials did not involve this product, and our capsules provide a much lower dose, 1,208 mg. See our guide collagen and joints.
Choosing wisely, with your doctor
Your doctor takes into account the stage of osteoarthritis, your other medical conditions, your treatments, and what you have already tried. The table summarizes the data from this guide.
| Option | Measured Effect | Timeline and Duration | Level of Evidence |
|---|---|---|---|
| Exercise | −12 points of pain on 100 | At end of program, partially maintained 2 to 6 months | High, 44 trials |
| Weight Loss | Less pain with diet and exercise | 18 months in IDEA | Strong ACR recommendation |
| Injected corticosteroids | −0.40 on pain | Rapid, disappeared by 26 weeks | Weak according to Cochrane |
| Injected hyaluronic acid | −0.08 versus placebo | Maximal from 5 to 13 weeks, up to 6 months | Debated: OARSI case by case, ACR against |
| Oral hyaluronic acid | Benefit in a subgroup | At 2 and 4 months | Weak, small trials |
| Harpagophytum | Comparable to diacerein | 4 months | Moderate, on a single trial versus placebo |
| Turmeric, ginger, collagen | Small effects, sometimes none | 12 weeks to 6 months | Weak to moderate |
Hyaluronic acid injection is therefore mainly discussed after exercise, weight management, and first-line treatments, rather in mild to moderately advanced osteoarthritis. Our guide osteoarthritis: natural solutions completes this overview.
Consult promptly in case of warm, red and swollen knee, especially with fever; knee locking or giving way; pain after a fall; pain that wakes you at night or worsens despite rest; unexplained weight loss. Pain that limits walking for weeks deserves an evaluation.
200 mg of hyaluronic acid and 1,208 mg of hydrolyzed marine collagen type 1 Naticol® per day, with 160 mg of vitamin C and 3.96 mg of manganese, in 4 vegetable capsules to be taken with a large glass of water, all at once or spread throughout the day. One blister pack covers one month, and the formula can be taken year-round.
See Marine Collagen in capsulesFor your joints, also discover our Organic Harpagophytum, 1,200 mg of organic root per day.
Frequently asked questions
Is hyaluronic acid injection in the knee dangerous?
It is usually well tolerated: transient pain and swelling at the injection site are the most frequent reactions. Acute inflammatory reactions are rare, and joint infection, or septic arthritis, was recorded in at most 0.5% of patients within 90 days in a large cohort.
How long does the effect of a hyaluronic acid injection in the knee last?
The effect peaks between the 5th and 13th week and remains measurable up to 6 months. In a 40-month trial, repeated courses maintained it at least one year after the last course.
Is a single hyaluronic acid injection enough for the knee?
The data diverge: one meta-analysis found no significant effect of single injection versus placebo, another concluded results close to series data. Both have ties with manufacturers, and the protocol depends on the product chosen by the physician.
What should be avoided after a hyaluronic acid injection in the knee?
No cited study has tested this. As practical advice, following your physician's instructions: rest the knee for 24 to 48 hours, without intense sports or carrying heavy loads, then gradually resume activity. Fever, red, warm knee with significant swelling, or increasing pain require medical consultation.
Hyaluronic acid or corticosteroid infiltration: what to choose?
Corticosteroids work faster, with effects diminishing around 6 months; hyaluronic acid works more slowly but performs better than corticosteroids from week 12 to week 26. The American College of Rheumatology favors corticosteroids, while OARSI places both at the same level.
How long does hyaluronic acid take to work in the knee?
Compared to corticosteroids, it performs worse at 2 weeks, equal at 4 weeks, and better beyond week 8. Maximum benefit occurs between weeks 5 and 13.
Do hyaluronic acid infiltrations work on advanced osteoarthritis?
Trials primarily recruited grades 2 and 3. In a study of 102 patients, mild osteoarthritis, response to the first injection, and age 60 or older doubled the chances of response. For severe osteoarthritis, data are limited.
Can hyaluronic acid in capsules replace an infiltration?
No study has compared them: these are two different approaches. In the longest oral trial, 200 mg daily combined with daily quadriceps exercise performed better than placebo only in patients 70 years or younger, at 2 and 4 months.
Is PRP more effective than hyaluronic acid?
A meta-analysis of 18 trials gives it the advantage, 44.7% versus 12.6% improvement in WOMAC score. However, the RESTORE trial found no difference between PRP and saline solution at 12 months.
Can hyaluronic acid be injected again in the knee?
Yes, repeated courses have been studied: four courses of five injections over 40 months were well tolerated, with 80.5% responders versus 65.8% under placebo. Repeat treatment is decided with the physician, based on response to the previous course.
What do studies say about hyaluronic acid injections in the knee?
They are divided: pain decreases by 28 to 54% from baseline between weeks 5 and 13, but the difference with placebo injection is only 2 mm on 100 in large trials.
What else can be done alongside infiltrations to relieve knee osteoarthritis?
Exercise remains the basic treatment, with an advantage to quadriceps strengthening at least 3 times per week. If overweight, losing 5% of body weight or more can already improve symptoms. Harpagophytum, turmeric, ginger, and collagen have modest effects.
Sources
The studies cited below were identified via PubMed.
- Bellamy N, Campbell J, Robinson V, et al. Viscosupplementation in the treatment of knee osteoarthritis. Cochrane Database of Systematic Reviews, 2006;2006(2):CD005321. DOI
- Pereira TV, Jüni P, Saadat P, et al. Viscosupplementation in knee osteoarthritis: systematic review and meta-analysis. BMJ, 2022;378:e069722. DOI
- Oe M, Tashiro T, Yoshida H, et al. Oral hyaluronic acid relieves knee pain: a review. Nutrition Journal, 2016;15:11. DOI
- Temple-Wong MM, Ren S, Quach P, et al. Concentration and size distribution of hyaluronic acid in human knee synovial fluid: variations by age and cartilage degeneration. Arthritis Research & Therapy, 2016;18:18. DOI
- Navarro-Sarabia F, Coronel P, Collantes E, et al. A 40-month randomized, placebo-controlled multicenter study evaluating the efficacy and residual effect of repeated intra-articular injections of hyaluronic acid in knee osteoarthritis: the AMELIA project. Annals of the Rheumatic Diseases, 2011;70(11):1957-1962. DOI
- Hamburger MI, Lakhanpal S, Mooar PA, Oster D. Intra-articular hyaluronic acids: review of product-specific safety profiles. Seminars in Arthritis and Rheumatism, 2003;32(5):296-309. DOI
- Bannuru RR, Schmid CH, Kent DM, et al. Comparative effectiveness of pharmacologic treatments for knee osteoarthritis: a systematic review and network meta-analysis. Annals of Internal Medicine, 2015;162(1):46-54. DOI
- Rutjes AW, Jüni P, da Costa BR, et al. Viscosupplementation for knee osteoarthritis: a systematic review and meta-analysis. Annals of Internal Medicine, 2012;157(3):180-191. DOI
- Zhang W, Robertson J, Jones AC, et al. The placebo effect and its determinants in osteoarthritis: a meta-analysis of randomized controlled trials. Annals of the Rheumatic Diseases, 2008;67(12):1716-1723. DOI
- Saltzman BM, Leroux T, Meyer MA, et al. Therapeutic effect of intra-articular saline injections in knee osteoarthritis: a meta-analysis of level 1 evidence studies. The American Journal of Sports Medicine, 2017;45(11):2647-2653. DOI
- Kolasinski SL, Neogi T, Hochberg MC, et al. 2019 American College of Rheumatology and Arthritis Foundation recommendations for the management of osteoarthritis of the hand, hip, and knee. Arthritis & Rheumatology, 2020;72(2):220-233. DOI
- Bannuru RR, Osani MC, Vaysbrot EE, et al. OARSI recommendations for the non-surgical management of knee, hip, and polyarticular osteoarthritis. Osteoarthritis and Cartilage, 2019;27(11):1578-1589. DOI
- Bowman EN, Hallock JD, Throckmorton TW, Azar FM. Hyaluronic acid injections in knee osteoarthritis: predictive factors for success. International Orthopaedics, 2018;42(4):733-740. DOI
- Concoff A, Sancheti P, Niazi F, et al. Efficacy of multiple versus single hyaluronic acid injections: a systematic review and meta-analysis. BMC Musculoskeletal Disorders, 2017;18(1):542. DOI
- Vincent P. Intra-articular hyaluronic acid in symptomatic treatment of knee osteoarthritis: meta-analysis of single-injection products. Current Therapeutic Research, Clinical and Experimental, 2019;90:39-51. DOI
- Hummer CD, Angst F, Ngai W, et al. High molecular weight intra-articular hyaluronic acid in the treatment of knee osteoarthritis: network meta-analysis. BMC Musculoskeletal Disorders, 2020;21(1):702. DOI
- Bannuru RR, Natov NS, Obadan IE, et al. Time-dependent effect of hyaluronic acid versus corticosteroids in knee osteoarthritis: systematic review and meta-analysis. Arthritis and Rheumatism, 2009;61(12):1704-1711. DOI
- Jüni P, Hari R, Rutjes AW, et al. Intra-articular corticosteroids in knee osteoarthritis. Cochrane Database of Systematic Reviews, 2015;2015(10):CD005328. DOI
- Belk JW, Kraeutler MJ, Houck DA, et al. Platelet-rich plasma or hyaluronic acid in knee osteoarthritis: systematic review and meta-analysis of randomized controlled trials. The American Journal of Sports Medicine, 2021;49(1):249-260. DOI
- Bennell KL, Paterson KL, Metcalf BR, et al. Effect of intra-articular platelet-rich plasma injection versus placebo on pain and medial tibial cartilage volume in knee osteoarthritis: the RESTORE randomized trial. JAMA, 2021;326(20):2021-2030. DOI
- Gupta N, Khatri K, Lakhani A, et al. Long-term efficacy of intra-articular injections in knee osteoarthritis: systematic review and Bayesian network meta-analysis. Journal of Orthopaedic Surgery and Research, 2025;20(1):227. DOI
- Honvo G, Reginster JY, Rannou F, et al. Safety of intra-articular hyaluronic acid injections in osteoarthritis: systematic review and meta-analysis. Drugs & Aging, 2019;36(Suppl 1):101-127. DOI
- Fuqua A, Premkumar A, Jayaram P, Wagner C. Complications and opioid prescriptions after genicular nerve radiofrequency or intra-articular injection: matched cohort study. Regional Anesthesia and Pain Medicine, 2025;50(1):46-54. DOI
- Tashiro T, Seino S, Sato T, et al. Oral polymer hyaluronic acid alleviates symptoms of knee osteoarthritis: 12-month double-blind placebo-controlled study. The Scientific World Journal, 2012;2012:167928. DOI
- Wang SJ, Wang YH, Huang LC. Liquid association of hyaluronic acid, glucosamine, and chondroitin as a dietary supplement in patients suffering from knee osteoarthritis with moderate pain: a randomized controlled trial. Medicine, 2021;100(40):e27405. DOI
- Fransen M, McConnell S, Harmer AR, et al. Exercise in knee osteoarthritis. Cochrane Database of Systematic Reviews, 2015;2015(1):CD004376. DOI
- Juhl C, Christensen R, Roos EM, et al. Influence of exercise type and dose on pain and disability in knee osteoarthritis: a systematic review and meta-regression of randomized controlled trials. Arthritis & Rheumatology, 2014;66(3):622-636. DOI
- Messier SP, Gutekunst DJ, Davis C, DeVita P. Weight loss reduces knee joint loads in overweight or obese older adults with knee osteoarthritis. Arthritis and Rheumatism, 2005;52(7):2026-2032. DOI
- Messier SP, Mihalko SL, Legault C, et al. Effects of intensive diet and exercise on knee loads, inflammation, and clinical outcomes in overweight or obese adults with knee osteoarthritis: the IDEA randomized trial. JAMA, 2013;310(12):1263-1273. DOI
- Gagnier JJ, Chrubasik S, Manheimer E. Harpagophytum procumbens in osteoarthritis and low back pain: a systematic review. BMC Complementary and Alternative Medicine, 2004;4:13. DOI
- Chantre P, Cappelaere A, Leblan D, et al. Efficacy and tolerability of Harpagophytum procumbens versus diacerhein in the treatment of osteoarthritis. Phytomedicine, 2000;7(3):177-183. DOI
- Vlachojannis J, Roufogalis BD, Chrubasik S. Systematic review of the safety of harpagophytum preparations in osteoarthritis pain and low back pain. Phytotherapy Research, 2008;22(2):149-152. DOI
- Wang Z, Jones G, Winzenberg T, et al. Efficacy of a Curcuma longa extract on symptoms and synovial effusion of knee osteoarthritis: a randomized trial. Annals of Internal Medicine, 2020;173(11):861-869. DOI
- Bartels EM, Folmer VN, Bliddal H, et al. Efficacy and safety of ginger in patients with osteoarthritis: a meta-analysis of randomized controlled trials versus placebo. Osteoarthritis and Cartilage, 2015;23(1):13-21. DOI
- Benito-Ruiz P, Camacho-Zambrano MM, Carrillo-Arcentales JN, et al. Randomized controlled trial on the efficacy and safety of a food ingredient, hydrolyzed collagen, to improve joint comfort. International Journal of Food Sciences and Nutrition, 2009;60(Suppl 2):99-113. DOI
- Bongers CCWG, Ten Haaf DSM, Catoire M, et al. Effect of collagen supplementation on pain in healthy individuals with knee complaints: a randomized controlled trial. Applied Physiology, Nutrition, and Metabolism, 2020;45(7):793-800. DOI
- García-Coronado JM, Martínez-Olvera L, Elizondo-Omaña RE, et al. Effect of collagen supplementation on osteoarthritis symptoms: meta-analysis of randomized placebo-controlled trials. International Orthopaedics, 2019;43(3):531-538. DOI
